Why Measuring Serum Levels of Estradiol (E2) is Pointless

Pharma / TRT Testosterone Replacement
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This should be made a sticky as most people don’t understand this concept. Many know that it is unwise to take an AI or block estrogen but they don’t know why.

When you get a blood test and measure your testosterone levels, you get a fairly accurate reading as testosterone is transported throughout your body via serum. This much you know.

The part you don’t realize is WHERE it is converted into estradiol (that thing everyone is so afraid of for no reason). That conversion, is done by an enzyme called aromatase. The conversion happens IN the tissue. Once converted, estradiol does NOT get transported around the body in the serum. It remains primarily in the tissue, skeleton, and brain.

When you are measuring serum levels, you are only seeing a TINY FRACTION of the estradiol that is leaking into the serum which doesn’t convey whatsoever the amounts everywhere else in the body. This is like measuring tiny drops of water leaking out of a bucket of water and making claims to how much water is in the bucket. It is absolutely and utterly pointless. This makes estradiol something called a paracrine hormone.

The other part is that every area of the body will have varying levels of estradiol. You can have a lot in one area and very little in another. This is a SELF REGULATING mechanism that the body does naturally. If you take an aromatase inhibitor, you are blocking the conversion of testosterone to estradiol. The problem is that you will have NO IDEA where it will be blocked. It could wind up being blocked just slightly in one area and perhaps blocking all of it in the brain. Taking even the slightest amount of an AI, I don’t care how small, will cause detrimental harm to your health over the course of time.

Symptoms that people claim to be “high E2 issues” are anything but. In the vast majority of cases they are due to hormone fluctuations caused by protocols that are not optimal for that given individual. This is virtually always resolved by ensuring two simple things:

  1. Ensuring that you inject often enough where you are no longer feeling any of the ups and downs during the week. If weekly injections aren’t working, try twice weekly and test over 6-8 weeks. If that doesn’t work try 3 times a week and test. If that doesn’t work you can even try daily (to ensure the most consistent and stable levels we can have). You need to find the frequency that works best for YOU. There is no right answer for this. I can only provide the strategy that works.

  2. Ensure your free testosterone levels are optimal. Don’t even bother with total as that is also a moot point. If you are symptomatic and free T is under 20 you will most likely require more (in the vast majority of cases). Most tend to feel better once they hit 30 (in the vast majority of cases). You MAY be different. You may need less or you may need more. I only report what the majority are doing to eliminate symptoms but this is just a guideline and could wind up being completely irrelevant for your specific case. Don’t target a specific number. Take more or less and determine where YOU feel best, whatever that dose is, until you are free of symptoms.

The video I did with Dr. Jordan Grant is the best example I have so far that explains this completely:

Once you watch it, don’t take his word for it. Read through the studies and medical literature that he provided, as evidence, that demonstrates what he is claiming (as well as what the rest of the doctors I deal with are claiming).

https://drive.google.com/drive/folders/1Ml3jnxdxpBTc3kKIIpW3KT5CqrwIdjuG

Until you can understand this concept you will never feel your best nor will you have your overall health as your priority.

Again, this is not opinion. Facts demonstrated by evidence.

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Great work here. I’ve appreciated your videos and the knowledge base your sharing. It’s been helpful. I can confirm wild “high e2” like symptoms seemed to be more fluctuations that were resolved with more frequent injections. Hopefully drs will catch up with all this soon.

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I wouldn’t mind the references, if you have them available. I don’t really want to watch the video, but my email is hardartery@gmail.com if you don’t want to post them. Unfortunately, this has been the theory kicking around my brain for a while but without being able to find the studies to really back it up. We’re not allowed to agree this frequently.

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@hardartery look at the link for the Google drive that I posted in the main thread. It’s right there.

In particular, look at the Estradiol as a Male Hormone article and look at the multitude of references at the bottom.

I don’t know how much more evidence I’m supposed to provide here.

https://drive.google.com/drive/folders/1Ml3jnxdxpBTc3kKIIpW3KT5CqrwIdjuG

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I missed that link. Only saw the video. Thanks.

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The more I research, the more convinced I become that most of these labs might be totally useless, including the measurement for free testosterone. The direct assay done by LabCorp is itself an estimate based on their usage of an analogue that competes with free testosterone for antibody receptor sites. Further reading shows that accuracy and relevance are debatable in any case, with mixed results coming from many studies.

I am beginning to understand why several men here, including @dextermorgan (and others) advise to treat the symptoms, and the measured serum levels be damned.

Hormone serum testing appears to me to be something like taking sporadic core samples in Antarctica and trying to make claims about the entire continent.

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The best analogy that I give for this is imagine if you were stuck on a deserted island with plenty of testosterone but no access to Labs. What would you do? You would figure out how often and how much you need to take until you felt better, right? That’s really all there is to it. Everyone looks at this thing as being so complicated with so many variables that need to be adjusted when it simply couldn’t be further from the truth.

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Good example. Treat the symptoms within sane constraints provided by things like CBC work ups and other obvious checks, such as PSA.

I do wonder if there is a remarkable difference between aromatization in men with high endogenous levels of testosterone, and men with “high” exogenous. Have you run across any info on what those differences might be?

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I can’t say that I have… I can definitely ask though. Logically, TRT in itself will not affect the amount of aromatase in the body, so if I had to make a somewhat educated guess I doubt there would be any difference between the two.

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I have seen this in some of the heavier guys, as visceral fat is reduced, as it often is with TRT, E2 drops with it. Initially, of course, E2 will elevate, but often returns to close to pre-TRT levels once the fat goes.

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Yes of course, but we’re talking strictly of the amount of aromatase a man would have if he had, say 1200 total natural vs 1200 total exogenous. Of course the T would increase muscle mass and decrease body fat which would reduce aromatase but that would be in BOTH cases.

My argument is: I have 1200 total T and I figure out how much aromatase I have with some magical aromatase detecting device. I then begin to take just enough exogenous T to ensure my levels remain at 1200 (adjusting daily to manage this as my natural levels get suppressed). Then I measure my levels of aromatase to see if they would have changed. Why would they change? Logically it wouldn’t make any sense for them to change.

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I know, that was not in direct context to your discussion, I just threw it in.

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I’m unclear on aromatase activity in general. I was wondering strictly from the standpoint of E2 production - testosterone aromatizing. As I understand it, E2 increases with Testosterone as there is more T to aromatize into E2 in the first place.

My question is whether there is a remarkable difference in this activity between endo/exo testosterone. For example, why are the reference ranges for E2 seemingly low when compared against TRT populations? Are they that different at all? Why isn’t a man with 1,200 (endogenous) total T aromatizing at a similar rate as a man achieving that serum T level exogenously (who is often prescribed AIs to counteract that activity)?

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It’s a good question. I’ll definitly ask around and see if anyone has looked into this.

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While the statement that estrogen levels differ between tissues the notion that E2 measurement in serum in general is pointless is not correct.

In biology what we do to study the function of a protein/enzyme is to modify the corresponding encoding gene. We either knockout the gene completely or we create an enzyme with higher or lower activity through targeted mutation and then study the resulting phenotype. Of course that’s not really possible with humans but we can study subjects carrying a ‚natural and viable‘ mutation in the eg gene encoding the aromatase enzyme.

Klinefelter syndrome is such an example where the aromatase enzyme is overexpressed in subjects due to a mutation in the ‚on/off‘ switch of the gene.
Now in those subjects estradiol is significantly increased in tissues but it’s also significantly increased in serum. This simple example illustrates that there is a correlation between the tissue concentrations and the serum levels; it’s not 1:1, it’s not perfect but it’s there and it can be used for diagnostic purposes.

The same is true for obesity related increase in E2 levels. Aromatase in fat tissue locally aromatises T to E but it again leaks into the serum and can be picked up there.

Another example is estrogen sensitive breast cancer in woman. AIs reduce local breast tissue E concentrations and this is again reflected in reduced serum levels.

Another example is that plasma E2 concentrations are directly related to the brain E2 levels in the pituitary which act as a negative feedback loop to LH secretion and thus T.

Long story short. Local estradiol concentrations differ between tissues, and serum E2 levels are surrogate measure useful in diagnostics.

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Because intra testicular aromatisation is circumvented in the TRT setting; this lowers E2 in TRT.
But high freeT concentrations after injecting high doses provide more substrate to the aromatase enzyme; this is increased E2 in TRT and that’s the basis for ‚microdosing‘

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I sent your comment to Dr. Grant. Here is his reply:

I will respond. He’s wrong about Klinefelters and aromatase. I’ve looked that up.

He’s missed the point on the serum e2. It isn’t driving tissue ACTION.

It is a surrogate for aromatase occurring. Yes. But that’s it. It doesn’t say where more or less aromatization is happening.

If local e2 concentrations differ (which they do) then one cannot how much each tissue contributes to serum level. Therefore NO argument for an AI can be made.

The e2/LH part doesn’t matter to those on TRT. And there is aromatase expressed in the hypothalamus as well, so they don’t know if the serum blood level is what is being monitored there.

Long story short, he’s said the same things I’ve said. Yet then uses those to say the serum e2 is active. It isn’t what is driving TISSUE action

It is USEFUL to simply show that aromatization is occurring. If VERY low, that is useful. (Most likely).

Multiple Klinefelter studies I’ve found with baseline characteristics do now show high e2. They show low e2 along with their low T.

Also in Klinefleters those guys typically have high LH and so the testes can still be PUMPING OUT estradiol directly. It isn’t “over aromatization”.

But I’m open to his studies showing that aromatase is globally increased in Klinefelter patients. I don’t see it. I have had guys with KS on testo and that was when I checked estradiol levels and they were never out of line with the test level.

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Klinefelter‘s is characterized by a mild absolute increase in estrogens and a significant relative hyperestrogenism due to an about fourfold increase in testicular aromatase.
I fully agree that in Klinefelters there is no systemic increase in aromatase as the overexpression appears to be limited to the testicles. I also agree that in a TRT setting Klinefelter patients do not show a lower T/E ratio as the said effect is limited to the testicles which are bypassed on TRT.

I am not saying that anyone should use an AI on TRT. What I am challenging is this general statement that measuring E2 is pointless.

Let’s do a thought experiment:
I has been shown that young men respond differently than older man to TRT with regards to aromatization. Young men have significantly higher T/E2 ratios than old men, ie older men seem to have more aromatase activity than young men.

One interpretation is that this lower T/E ratio in older men is due to an increased fat deposition in the blood vessel system (so artherosclerosis, plaque burden) therefore it’s only limited to serum and does not reflect tissue concentrations. So best to ignore.

Another way of interpretation would be that men have more visceral adipose tissue. This in turn is associated with higher serum E2 levels although it is locally aromatized in the fat tissue, so again a sort of crosstalk between tissue and serum. Or even more systemic higher aromatase activity in also other tissues - we simply don’t know. But my point is, that men on TRT tend to target ‚levels‘ if 20 year old men. Why not modifying aromatase activity to bring the T/E ratio to levels seen in young men (only applicable in the scenario where aromatization is systemically increased, and only meant as a provocative thought).

I have a hypothesis - not supported by any data. The reason why men need such high levels as 200 mg T per week might be because aromatase is saturated at one point leading to a higher T/E ratio. And it’s the T/E ratio which primarily determines symptoms.

Also if there was no equilibrium between serum and tissue (eg bone) why would estrogen supplementation work for the prevention/treatment of osteoporosis?

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Isn’t the saturation point for e2 only at very high doses? Not trt doses?

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Fig 2 and 3

https://academic.oup.com/jcem/article/95/8/3955/2597323

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